Z Gastroenterol. 2003 Apr;41(4):333-42. :
[Alcoholic liver disease]
[Article in German]
Stickel F, Seitz HK, Hahn EG, Schuppan D.
Medizinische Klinik I und Poliklinik, Friedrich-Alexander-Universitat Erlangen-Nurnberg.
felix.stickel@med1.imed.uni-erlangen.de
Alcoholic liver disease is the most frequent organ damage encountered in chronic alcoholics and the annual death rate attributed to alcohol-induced end-stage liver disease exceeds that of car accidents. Alcoholic liver damage occurs mainly due to the toxicity of its first metabolite acetaldehyde, and due to interactions with numerous macro- and micronutrients. Established treatment options comprise psychotherapy aiming to achieve abstinence, nutritional therapy, management of hepatological complications, and liver transplantation in selected individuals. Since these therapeutic approaches are unsuccessful in many patients, pharmacological therapies of alcoholic liver disease are being investigated. Many drugs failed to be beneficial or have even shown toxicity. However, some agents are promising, such as S-adenosyl-L-methionine (SAMe), pentoxifylline, metadoxin, polyenylphosphatidylcholine or inhibitors of the cytochrome P450 2E1 isoenzyme. In severely ill patients with alcoholic hepatitis, drugs with anti-tumor necrosis factor alpha activity are currently investigated in clinical trials. If and how far corticosteroids are beneficial remains controversial and their use should be restricted to selected patients. Anabolic steroids used to enhance the nutritional status may lead to serious side effects while having a marginal benefit. Silymarin has not been proven efficacious in alcoholic cirrhosis and clinical trials are ongoing which aim to elucidate its therapeutic value in less advanced stages of liver disease.
Influence of SAMe on the modifications of brain polyamine levels in an
animal model of depression.
The mechanism(s) of the antidepressant activity of S-adenosyl-L-methionine (SAMe) have not
yet been elucidated. SAMe is essential for the synthesis of polyamines, which have a key role in
protein synthesis, cell proliferation, and neuronal plasticity. On the other hand, accumulating data
indicate that depression is associated with a reduction in regional brain volume and that
antidepressants increase neurogenesis in defined brain regions and also influence neuronal
plasticity. Here we show that in a validated rat model of depression (chronic unpredictable mild
stress-induced anhedonia) there is a significant reduction of putrescine, spermidine and spermine
in the hippocampus, and of only putrescine in the nucleus accumbens septi. SAMe, at a fully
antidepressant dose (300 mg/kg i.m., daily for 7 days), completely restores the levels of
putrescine in the nucleus accumbens, and restores in part the levels of both spermidine and
spermine in the hippocampus. These results may suggest (i) a role for brain polyamines in
depression and in reward processes, and (ii) that the antidepressant effect of SAMe may be due,
at least in part, to a normalization of putrescine levels in the nucleus accumbens septi.
[ Stress-induced dynamic changes in mouse brain polyamines. Role in
behavioral reactivity
Recent findings indicate that rapid and transient changes in polyamine metabolism, termed the
polyamine-stress-response, may occur repeatedly in the brain after chronic intermittent stress.
Here, we sought to examine the effects of chronic intermittent restraint stress, or of daily
intraperitoneal dexamethasone injections on polyamine concentrations in the hippocampus of
adult male C57BL/6 mice. Additionally, we studied the effects of alpha-difluoromethylornithine,
an irreversible ornithine decarboxylase inhibitor, on stress-induced changes in polyamines and on
behavioral reactivity to novelty stress measured in an open-field arena. As previously observed,
following a single stress episode putrescine concentration increased transiently, but the
polyamines spermidine and spermine remained unchanged. Following chronic restraint stress,
putrescine concentration was increased after each daily stress episode with the largest increase
observed after the 4th episode, while spermidine was increased just after the 2nd and 4th
episodes and spermine only after the 4th daily episode. In contrast, all polyamine concentrations
were increased after 10 injections of either dexamethasone or vehicle (0.9% NaCl). A 14-day
course of alpha-difluoromethylornithine treatment resulted in a complete putrescine depletion and
over 50% reduction in polyamines, and led to changes in open field activity indicative of altered
emotional behavior. CONCLUSIONS: (a) while putrescine concentration increases in the
hippocampus after each restraint stress episode, spermidine and spermine undergo a delayed but
transient increase; (b) in contrast, chronic dexamethasone treatment may lead to a permanent
increase in the concentrations of all polyamines and; (c) chronic alpha-difluoromethylornithine
treatment reduces brain polyamine concentrations and modulates emotional reactivity to novelty
stress. The study indicates that the brain polyamine-stress-response is a dynamic process that
varies with the type, intensity and length of stressful stimuli, and implicates this response as an
adaptive mechanism in the reaction to stressors.]
{ Melatonin attenuates the changes in polyamine levels induced by systemic
kainate administration in rat brains
Systemically administered kainate has been demonstrated to induce neuronal damage and
changes of the levels of biochemical substances related to neurotoxicity. Polyamines are thought
to be important in the generation of edema and neuronal cell loss associated with various type of
excitotoxicity. Melatonin exerts potent free radical scavenging, antioxidant, and neuroprotective
properties. This study was designed to estimate the effect of exogenous melatonin administration
on the changes of polyamine levels in rat brains after systemic administration of kainate. Kainate
[10 mg/kg, intraperitoneally (i.p.)] was injected into the rats to produce excitotoxicity. Melatonin
(15 mg/kg, i.p.) was administered 1 h before, immediately after, and 1 h after kainate treatment.
We examined the polyamine [putrescine (PU), spermidine (SD) and spermine (SM)] levels in the
cerebral cortex and hippocampus and neuronal density in the hippocampal CA1 and CA3
subsectors in brain sections. PU levels were increased 8 and 24 h after kainate treatment and the
administration of melatonin attenuated these changes. Only minor changes were noted in the
levels of the polyamine SD and SM after the kainate treatment. In histology, neuronal injuries in
the hippocampal CA1 and CA3 subsectors were examined 3 days after kainate treatment and
melatonin reduced the kainate-induced neuronal injuries. Our results show that melatonin inhibits
the polyamine responses in the cerebral cortex and hippocampus following kainate-induced
excitotoxicity and PU may be responsible for the protective effect of melatonin against
kainate-induced excitotoxicity.}
Mov Disord 2000 Nov;15(6):1225-9
S-Adenosyl-Methionine improves depression in patients with Parkinson's
disease in an open-label clinical trial.
Di Rocco A, Rogers JD, Brown R, Werner P, Bottiglieri T.
Department of Neurology, Beth Israel Medical Center-Albert Einstein College of Medicine, New
York, NY 10003, USA.
We report a pilot study of S-adenosyl-methionine (SAM) in 13 depressed patients with Parkinson's
disease. All patients had been previously treated with other antidepressant agents and had no
significant benefit or had intolerable side effects. SAM was administered in doses of 800 to 3600
mg per day for a period of 10 weeks. Eleven patients completed the study, and 10 had at least a
50% improvement on the 17-point Hamilton Depression Scale (HDS). One patient did not improve.
Two patients prematurely terminated participation in the study because of increased anxiety. One
patient experienced mild nausea, and another two patients developed mild diarrhea, which resolved
spontaneously. The mean HDS score before treatment was 27.09 +/- 6.04 (mean +/- standard
deviation) and was 9.55 +/- 7.29 after SAM treatment (p < 0.0001). Although uncontrolled and
preliminary, this study suggests that SAM is well tolerated and may be a safe and effective
alternative to the antidepressant agents currently used in patients with Parkinson's disease.
1: Nutrition 1998 Jul-Aug;14(7-8):605-10
Related Articles, Books, LinkOut
Immunonutrition: role of sulfur amino acids, related amino acids, and
polyamines.
Grimble RF, Grimble GK.
Institute of Human Nutrition, University of Southampton, UK.
Pro-inflammatory cytokines mediate widespread changes in protein metabolism. Amino acids
released from peripheral tissues fulfill a number of functions. They act as substrate for acute phase
protein and immunoglobulin synthesis and, together with polyamines, in the replication of immune
cells. Demands for specific amino acids may outstrip the supply from endogenous sources. A
number of strands of evidence suggest that sulphur amino acids, and amino acids that are
metabolically related to them, may be required in increased amounts. Protein deficiency impairs the
acute phase response. However, sulfur amino acid insufficiency compromises glutathione synthesis,
to a greater extent than hepatic protein synthesis, in the presence and absence of an inflammatory
stimulus. The resulting effect may be compromised antioxidant defences. Functioning of T cells is
dependent on intracellular glutathione concentrations and may also be affected by sulphur amino
acid insufficiency. It has been suggested that the increased N excretion, which occurs during the
immune response, is a reflection of a relative imbalance in the profile of amino acids released from
peripheral tissues and the requirements imposed by the synthesis of substances involved in the
acute phase response. Phenylalanine, tyrosine, tryptophan serine, and cysteine are released in
amounts closest to requirements. Polyamine synthesis may be important for the fidelity of the
enhanced level DNA transcription and RNA translation that occurs in response to infection and
during tissue repair, gut growth after surgery, and in gut barrier functions. Although synthesized de
novo from ornithine, arginine and S-adenosyl methionine (SAM), substantial recycling is a key
feature of polyamine metabolism. The recycling may be a reflection of the need to maintain
adequate tissue SAM during periods of rapid cell growth. During an immune/inflammatory response
the combination of enhanced utilization of cysteine for glutathione synthesis and cell replication may
lead to depletion of cellular SAM. A relatively small addition of polyamines to the diet may improve
gut-associated aspects of the hosts' antibacterial defenses.
Taken for two decades by Europeans as a remedy
for depression and arthritis, SAMe (pronounced
"sammy," short for S-adenosylmethionine) was
introduced in the U.S. in March of last year. Its
supporters maintain this natural supplement can
alleviate the symptoms of depression safely and
more rapidly than standard antidepressants. And in
the case of SAMe, these claims are backed by
some convincing data.
SAMe is a naturally occurring compound that
regulates the action of key brain chemicals such as
serotonin and dopamine, which may play a role in
combating depression. It also generates enzymes
that may help repair joints and the liver.
SAMe was discovered by Italian scientists in 1952,
and much of the research on the compound and its
possible benefits has been conducted in Italy and
other European countries. Because it's being
marketed as a supplement in the U.S., SAMe has
not been subjected to the rigorous clinical testing
required for FDA approval. However, it has been
evaluated over the years as a treatment for
depression, arthritis, and certain forms of liver
disease in dozens of European trials involving
thousands of patients. Approved as a prescription
drug in Italy, Germany, Spain, and Russia, SAMe
has been given successfully for two decades
without producing any significant adverse effects,
though mild digestive upset occasionally occurs.
Banishing the blues
Levels of SAMe are lower than normal in many
people with depression, and a 1994 study by
University of California researchers found that as
the symptoms of depression eased, SAMe blood
levels rose. Also in 1994, a major review in Acta
Scandinavica Neurologica evaluated the results of
more than a dozen clinical trials of SAMe for
depression. This analysis revealed that SAMe was
consistently more effective than a placebo in
relieving depressive symptoms and that its efficacy
was comparable to that of standard
antidepressants. It appears that about 70% of
depressed patients respond to SAMe, roughly the
same proportion that benefit from treatment with
the tricyclics or newer antidepressants such as
Prozac.
Two important pluses for SAMe: It doesn't cause
the side effects that have been linked to
antidepressant drugs, including dry mouth, blurred
vision, headache, drowsiness, insomnia,
nervousness, and poor sexual function; and it
typically works much more rapidly than the
prescription drugs. "Most people taking SAMe see
some effect within 10 days," says Baylor
University's director of neuropharmacology,
Teodoro Bottiglieri, Ph.D. By contrast, people often
have to take standard antidepressants for several
weeks--even a month or more--before the clouds
of depression start to lift.
Although those with mild mood problems might well
benefit from a trial of SAMe, experts caution that
anyone experiencing serious depression should use
the supplement only under the supervision of a
physician or psychiatrist. In addition, SAMe should
not be taken by anyone with manic depression
(bipolar disorder), because it may intensify the
manic "up" episodes.
Easing arthritis pain
There is also evidence that SAMe can foster joint
health by preserving the gellike, shock-absorbing
nature of cartilage, and it may even help repair
damaged cartilage. That SAMe could relieve more
than low spirits became apparent when some
individuals who had been taking the compound for
depression reported an unexpected bonus--relief
from painful and often long-standing symptoms of
osteoarthritis.
More than a decade ago, a large trial in Italy found
that SAMe was more effective than a placebo, and
as effective as the NSAID pain reliever naproxen, in
relieving the pain of osteoarthritis. It also appeared
to be safer, causing none of the stomach bleeding
that occurs in some patients taking NSAIDs.
Protecting the Liver
Ongoing research suggests that SAMe may be
effective for liver disease. SAMe is the body's major
source of glutathione, sometimes dubbed the
"master antioxidant," a substance that detoxifies
harmful compounds and helps repair liver damage.
By boosting glutathione levels, SAMe protects
tissues from damage by oxygen free radicals. For
example, a controlled trial in Spain (Journal of
Hepatology, 6/99) found that long-term use of
SAMe may delay the need for a liver transplant and
improve survival rates in patients with
alcohol-induced cirrhosis. Some doctors combine
SAMe with the herb milk thistle for serious liver
ailments; further study is needed.
Easing fibromyalgia
SAMe has also shown promise in treating
fibromyalgia. A 1991 European study that compared
SAMe with a placebo in 44 fibromyalgia sufferers
found the supplement eased symptoms of the
disorder, including pain, fatigue, and depression.
Suggested dose: SAMe is sold in 200 mg pills; it is
quite costly, ranging from around $1 to $2 per pill.
Take twice a day, an hour before breakfast and
lunch for best absorption. Also take folic acid (800
mcg a day) and vitamin B12 (1,000 mcg a day)
because SAMe will not work when levels of these
vitamins are low. Depression: Start with 200 mg
twice daily (400 mg a day); gradually increase, if
necessary, to 800 or even 1,600 mg a day.
Arthritis: 400 to 800 mg a day. Liver ailments:1,200
mg a day. Fibromyalgia: 800 mg a day.
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